The human retina is susceptible to damage from a variety of environmental factors, including laser light impact and other trauma, as well as disease. Once damaged, the cells responsible for capturing light energy and transducing it into a neural signal, the photoreceptors, do not regenerate. In fact, none of the neural cells of the retina can yet be made to readily regenerate in the adult human. When damage is severe enough, there is permanent vision loss in an area. Healthy photoreceptors do not migrate long distances toward the damaged area to replace damaged ones.
If the affected region is in the central macula, known as the fovea, then the ability to see fine detail, read at rapid rates, or recognize objects at great distances may be lost. The peripheral areas of vision do not have sufficient sampling density to perform these tasks to the same degree. Thus, early detection and treatment of potentially sight-robbing damage are crucial in maintaining central vision.
One of the chief problems in early detection of damage has been the difficulty of imaging a small area of retina. The macula presents a small target—6000 microns. The portion that is necessary for seeing damage that precludes observation of fine detail and reading is even smaller, about 600 microns. To examine this latter portion properly, it is desirable to image the central 20 degrees of the macula with sufficient magnification and contrast to determine whether an individual is at risk for permanent vision loss.
The opthalmoscope or fundus camera has traditionally been used to view and image the retina. Originally, these devices flooded the retina with white light. Subsequent devices have used selective wavelengths that have been found suitable for viewing or imaging particular structures or contrast between structures. Regardless of the wavelength of light used, many of the past devices used flood illumination, producing images of the retina that often are subject to poor contrast due to long range scatter. The long range scatter problem was identified to occur, not only from out of plane tissues, but also from the biological tissues that are inherently scattering, especially those within and near the retina.
One well-known method of reducing the long range scatter problem is to replace a flood illumination source with a scanning illumination source. Some research has suggested that the use of a double scanning optical apparatus that scans both incident and reflected light using a horizontal scanning element may be desirable. Scanning with such an element can be performed by a rotating multifaceted polygonal reflector, and a vertical scanning element, such as a reflecting galvanometer. Such an instrument is able to provide a two-dimensional output representative of reflection characteristics of the eye fundus. See, e.g., U.S. Pat. Nos. 4,768,873 and 4,764,005, as well as U.S. Pat. No. 4,768,874, each disclosing a laser scanning opthalmoscope in which a line beam is scanned across an eye. Such improvements have greatly increased the contrast of the images produced, but typically require expensive, heavy equipment that must be operated by a specialist.
Improvements on the scanning illumination source technology have been embodied in the use of advanced reflectometry techniques with a scanning laser opthalmoscope (“SLO”) as developed by the inventor, Ann Elsner, and colleagues. See, for example, Elsner A. E., et al., Reflectometry with a Scanning Laser Opthalmoscope, Applied Optics, Vol. 31, No. 19 (July 1992), pp. 3697-3710 (incorporated herein by reference). The SLO is advantageous for quantitative imaging in that a spot illumination is scanned in a raster pattern over the fundus, improving image contrast significantly over flood illumination. The inventor's SLO technology can further minimize unwanted scattered light by using confocal apertures such as a circle of variable diameter or annular apertures, depending on the desired mode of imaging. Once the light is returned through the confocal aperture, the desired light can then be transmitted to a detector. However, the optics used in confocal apertures can increase the complexity of the system, and high quality optics are an added expense. Therefore, a method for reducing or eliminating unwanted scattered light in a more cost effective manner would be greatly appreciated.
Regardless of whether scanning or flood illumination is used, both the illumination and imaging light in retinal imaging pathways must pass through the pupil of the eye. In addition to scattered light, strong reflections from the anterior segment of an eye and from lenses in the device must be minimized in the image so that they do not mask the weaker retinal imaging light of interest. The Gullstrand Principle, in which the incoming illumination light is spatially separate from the outgoing imaging light at a conjugate pupil plane, is usually used in ophthalmic imaging systems to minimize reflections from reaching the detector. An early Zeiss flood illumination fundus camera successfully incorporated the Gullstrand Principle by using a ring-shaped illumination beam at the pupil. In this, and many other flood illumination fundus camera designs, the useful imaging light backscattered from the retina is present in the center of the ring at the pupil, and is extracted using a circularly symmetric aperture (pinhole, or iris). See, e.g. B. Bengtsson, et. al., Some Essential Optical Features of the Zeiss Fundus Camera, Acta Ophth., Vol. 55, No. 1, (1977) pp. 123-131 (incorporated herein by reference). A specific method to separate the illumination and detection pathways, typically in the plane of the pupil, is the use of two, non-overlapping regions placed side-by-side, which removes the unwanted reflections. See, for example, Van Norren D, et al., Imaging retinal densitometry with a confocal Scanning Laser Opthalmoscope, Vision Res., Vol. 29, No. 12 (1989), pp. 1825-1830, (incorporated herein by reference). This method is not as light efficient as radially symmetric pupil separation techniques, which are desirable to preserve the weak return from the retina. It also does not take into consideration the maximization of optical image quality, which would be degraded in a wide field of view implementation due to the asymmetry of the illumination and imaging fan of scanning rays with respect to the optical axis, as defined by the alignment of the optics in the imaging system.
Unlike flood illumination fundus cameras, point-scanning retinal imaging systems have traditionally used a reversed illumination-imaging pupil, whereby the center of the pupil is used for illumination. See for example, R. H. Webb, et. al., Scanning Laser Opthalmoscope, IEEE T. Biomed, Eng., Vol. BME-28, No. 7, (July, 1981), pp. 488-492, (incorporated herein by reference). This is made possible due to the high irradiance provided by a laser source. However, due to the flatter central region of the cornea, this configuration is more susceptible to stray reflections reaching the detector than a system in which the light enters the pupil nearer its edge. In addition, to prevent unwanted reflections from reaching the detector, scanning retinal imaging systems with central illumination often use fixed apertures such as tape, metal, or ink; polarizing elements; or the tilt of optical elements. These approaches typically require time-intensive alignment and testing to verify reflection-free imaging and are often unique to each system built.
Unlike point-scanning laser opthalmoscopes (SLOs), line-scanning laser opthalmoscopes (LSLOs) illuminate the retina with a line and require only one slow scanning element to sweep the line across the field of view. As with standard SLOs, LSLOs must also deal with pupil reflections, and implementations have been reported that achieve illumination-imaging light separation at the pupil plane side by side, as well as LSLOs that split the imaging light in two and send each to a separate detector for stereo-based imaging. See, for example, C. J. Koester, Scanning mirror microscope with optical sectioning characteristics: applications in opthalmology, Appl. Opt., Vol. 19, No. 11, (June, 1980), pp. 1749-1757; A. E. Elsner, U.S. Pat. No. 7,331,669, Device for digital retinal imaging; and D. X. Hammer, et. al., Line-scanning laser opthalmoscope, J. Biomed. Opt., Vol. 11, No. 4, (July/August, 2006), pp. 041126-1-041126-10 (incorporated by reference herein). For wide-field LSLOs, a side-by-side pupil separation becomes no longer practical due to the resulting curvature of the illumination and imaging line. The problem of line curvature is apparent in a confocal line-scanning system, since a curved illumination slit will not pass through a narrow linear aperture to the detector, which causes a loss of imaging light and a correspondingly restricted field of view. A method of pupil separation in a line-scanning system that removes unwanted reflections in a reliable and cost-effective manner, minimizes slit curvature by keeping all optical elements on-axis with respect to the illumination and imaging light, and enables simple optical alignment for wide-field imaging systems, would thus be greatly appreciated.
Further improvements to increase contrast in retinal imaging systems include the extensive use of near infrared light as an illumination source, in lieu of other wavelengths or color images, as developed by the inventor and colleagues and described in Elsner, A. E., et al., Infrared Imaging of Sub-retinal Structures in the Human Ocular Fundus, Vision Res., Vol. 36, No. 1 (1996), pp. 191-205; Elsner, A. E., et al., Multiply Scattered Light Tomography: Vertical Cavity Surface Emitting Laser Array Used for Imaging Subretinal Structures, Lasers and Light in Opthalmology, 1998; Hartnett, M. E. and Elsner, A. E., Characteristics of Exudative Age-related Macular Degeneration Determined In Vivo with Confocal and Indirect Infrared Imaging, Opthalmology, Vol. 103, No. 1 (January 1996), pp. 58-71; and Hartnett, M. E., et al., Deep Retinal Vascular Anomalous Complexes in Advanced Age-related Macular Degeneration, Opthalmology, Vol. 103, No. 12 (December 1996), pp. 2042-2053 (all of which are incorporated by reference herein). Combining infrared imaging with SLO allows the use of reflectometry techniques to view the eye rapidly and noninvasively because infrared light is absorbed less than visible light and scatters over longer distances. Further, when implemented with scanning laser devices, infrared and near infrared imaging of sub-retinal structure in the ocular fundus has been able to reveal sub-retinal deposits, the optic nerve head, retinal vessels, choroidal vessels, fluid accumulation, hyperpigmentation, atrophy, and breaks in Bruch's membrane—features that have proven difficult or impossible to observe with flood illumination devices. In addition, because infrared illumination is absorbed by the tissues less than other wavelengths, much less illumination from the source is required to create a high contrast image.
The improvements noted above, and methods for successfully imaging small retinal features were combined in U.S. Patent Application No. 60/329,731; Ser. No. 10/493,044; 60/350,836; and PCT Application No. PCT/US02/32787, incorporated by reference herein. In addition, discussions of using the techniques for detecting and localizing such features are described in the publications of the inventor and colleagues: Elsner, A. E., et al., Infrared Imaging of Sub-retinal Structures in the Human Ocular Fundus, Vision Res., Vol. 36, No. 1 (1996), pp. 191-205; Elsner, A. E., et al., Multiply Scattered Light Tomography: Vertical Cavity Surface Emitting Laser Array Used For Imaging Subretinal Structures, Lasers and Light in Opthalmology, (1998); Elsner, A. E., et al., Foveal Cone Photopigment Distribution: Small Alterations Associated with Macular Pigment Distribution, Investigative Opthalmology & Visual Science, Vol. 39, No. 12 (November 1998), pp. 2394-2404; Hartnett, M. E. and Elsner, A. E., Characteristics of Exudative Age-related Macular Degeneration Determined In Vivo with Confocal and Indirect Infrared Imaging, Opthalmology, Vol. 103, No. 1 (January 1996), pp. 58-71; and Hartnett, M. E., et al., Deep Retinal Vascular Anomalous Complexes in Advanced Age-related Macular Degeneration, Opthalmology, Vol. 103, No. 12 (December 1996), pp. 2042-2053, incorporated by reference herein. The systems and techniques described in the inventor's previous patent applications introduced a moderately priced, portable system that provided a high contrast, digital image of the eye that could be used by non-specialists, such as paramedics or other individuals in the field. However, creating a system that is even less expensive, uses standard digital imaging technology, includes fewer high precision optics to obtain a high contrast image would be greatly appreciated in the art.
In one method for determining the noise present in a camera, (Bahkle, Method and apparatus for dark frame cancellation for CMOS sensor-based tethered video peripherals, U.S. Pat. No. 6,061,0992) a mechanical shutter is combined with a CMOS detector, in which the purpose and embodiments of combining these elements are completely different from those in this application. The shutter described in Bakhle is completely open (i.e., unused) during acquisition of the scene image, and all pixels of the CMOS camera are exposed simultaneously for the same length of time and retained for use in later image processing. When the shutter is used, the resulting signal determines the noise level at different locations or pixels in the camera, in the manner well-known from CCD applications. In Bakhle, the mechanical shutter is completely closed for the acquisition of a dark image, which is then used to remove noise in the scene image, and there is no mention of an electronic rolling shutter. The electronic shutter of the present application makes unnecessary the use of a mechanical aperture. Further, the use of a rolling shutter is not advised, even discouraged, whenever moving targets are imaged, because of the well known CMOS sensor artifact because there is not the sample and hold availability for the whole sensor that is found in a CCD. In fundus imaging, eye movements can induce distortions when a rolling shutter is used, as opposed to a global shutter-like exposure such the flash illumination used in fundus camera-like devices, which requires the CMOS to use limited sampling durations.
In addition, studies have shown that the multiply scattered light images that are used to reveal structures in the deeper retina can provide more detailed images, providing additional diagnostic utility. Further, the use of the infrared spectrum can be used to image the retina without dilation of the patient's pupils, and the added potential for using multiply scattered light, particularly in cases in which the target of interest is underneath a highly reflective layer, allow visualization of features difficult to see otherwise. However, previous scanning devices, do not readily utilize this method for producing an image without scanning not only the light illuminating the target, but also scanning the light returning from the target to the detector, which requires considerable care. Therefore, a moderately priced, portable digital retinal imaging device that is capable of producing multiply scattered light images would be greatly appreciated.
Existing devices specifically designed for screening of retinal disease that use flood illumination with bright lights of shorter wavelengths, and typically acquire single images at slow rates, have been shown recently to provide an unacceptable percentage of gradable images in the hands of technicians (Zimmer-Galler I., et. al., Results of implementation of the DigiScope for diabetic retinopathy assessment in the primary care environment, Telemed. J. E. Health, Vol. 12, No. 2, (April, 2006), pp. 89-98), regardless of the duration of training (Ahmed J, et. al., The sensitivity and specificity of nonmydriatic digital stereoscopic retinal imaging in detecting diabetic retinopathy, Diabetes Care, Vol. 29, No. 10, (October, 2006), pp. 2205-2209). As discussed above, the embodiments of the present application address the issue of inconsistent use in the eye field. Other issues addressed by embodiments of the present application include onboard pre-processing of image and instrument parameter data for quality assurance and ease of use, addressing the issue of alignment of the instrument with respect to the target (e.g., small pupils and addressing and other issues regarding the anterior segment of the eye) and addressing the issue of alignment of optical components within the instrument to remove strong undesired reflections from the anterior segment of the eye in both a reliable and cost-effective manner. The present application further addresses the prior art issue of failing to capture the images of the best existing quality, and failing to operate the instrument with optimal parameters.
Therefore, a moderate cost, portable retinal imaging device that provides for the use of a scanning laser device operating with near infrared illumination and which can allow for multiply scattered light would be appreciated in the art. Further, such a device that would allow for increased ease of use by allowing a greater field of view than just 20 deg visual angle, greater field of view without sacrificing spatial resolution, greater field of view without undesired reflections, greater field of view for superimposing visual stimuli and retinal locations, as well as utilizing a non-proprietary system for producing and saving the digital image, would be greatly appreciated.